protonation and solvent effects on a resorcin[4]arene
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Protonation and solvent effects on a resorcin[4]arene based cavitand
A Senior Honors Thesis
Presented in Partial Fulfillment of the Requirements for Graduation with Distinction in Chemistry in the Undergraduate College of Mathematical and Physical Sciences of
The Ohio State University
By
Dennis Hansel Mayo
The Ohio State UniversityJune 2006
Project Advisor: Professor Jovica D. Badjić
2
Abstract
In these studies, we are interested in the effects of solvent polarity and pH on the
conformation of a resorcin[4]arene based cavitand. Synthesis of the cavitand was
successfully accomplished in nine steps. The cavitand was shown to adopt two
conformations by 1H NMR spectroscopy. These two conformations are vase and kit like,
interconverting fast on the 1H NMR time scale. By titration of an acid and a polar solvent
to a solution of our cavitand, we discovered (via 1H NMR spectroscopy) that the
conformational changes can indeed be controlled. Such changes in conformation are
envisioned to be used in the design of stimuli-responsive systems for applications in the
fields of drug delivery, chemical detection, and catalysis.
3
Acknowledgements
Dr. Jovica D Badjić, for providing me such a great opportunity to perform research in his group for the past 2 years, allowing me the freedom to work by myself, and introducing me to the field of supramolecular chemistry.
Drs. Jon R. Parquette and Leo A. Paquette, for teaching me so much in their Honors Organic Laboratory courses and peaking my interest in synthetic organic chemistry, and JRP for attending my oral defense.
Dr. Peng George Wang, for attending my oral defense.
Dr. Zhiqing Yan, for collaborating with me, giving me support and advice, teaching me numerous methods, and for teaching me about China and his culture.
Dr. Veselin Maslak, for sharing his benchtop expertise.
Troy McCracken, for giving me an ear to complain to, helping me with problems, sharing a laugh, and playing 80’s rock on the radio.
All our other lab members: Matt Gardlik, Rachael Ricart, Chris Baddeley, Steve Riech, Yuning Chang, Chad Eichman, and Puneet Devgun, for giving me support.
My parents, for supporting me always in any and every thing I do.
My roommates, for never letting me take myself too seriously, and waiting for me to get home from lab before they leave for the bars.
Lastly, Katie Stanek, my wife-to-be. Thank you for always being there for me and supporting me, even when you have no idea what I am talking about. You always give me something to look forward to when I get home. Le grá go deo.
4
Table of contentsSection Page
ABSTRACT 2
ACKNOWLEDGMENTS 3
INTRODUCTION 5
RESULTS AND DISCUSSION 14
1H NMR TITRATION EXPERIMENTS 17
CONCLUSIONS AND FUTURE WORK 19
EXPERIMENTAL 21
REFERENCES 28
5
Chapter I. Introduction
In nature, many chemical transformations occur in enzymes. Within these
enzymes are cavities which mediate the transformation. Many steps of such
transformations are results of conformational changes within the enzyme itself. By
constructing synthetic cavities, we can mimic conditions that occur in nature. Molecular
vessels such as cavitands, cyclotriveratrylenes, carcerands, velcrands, trinacrenes, self-
assembled capsules, and metal-assembled cage molecules have been constructed to
selectively recognize and surround a target molecule. These synthetic vessels hold the
target molecule and protect it from its external environment. They also can transport the
guest molecule between phases, and can mediate chemical transformations. However, it
is difficult to control uptake and release of guest molecules selectively. Thus far, the best
results have been afforded by hemi-carciplexes(1) and metal-containing molecular
cages(2). Similar results are afforded in the case of cylindrical capsules formed by the
dimerization of a cavitand(3). However, it is still difficult to control the kinetics of the
guest’s movement in and out of its host. It has been shown that by controlling the
conformation of a host molecule via hydrogen bonding, the exchange and release of guest
molecules can be controlled(4). By controlling the conformation of the capsule, it is
certainly plausible that one could: 1) control the uptake and release of guest molecules, 2)
develop new molecular devices for delivering guest molecules and 3) create synthetic
channels allowing transport of ions of whole molecules across membranes. In this light,
we have been seeking to build molecular containers that are responsive to external
stimuli.
6
Conformational changes in supramolecular assemblies are desired to be tunable
by external inputs. These external inputs can include, but are not limited to, acid/base
chemistry(5), ligand-to-metal coordination, and redox chemistry. For example,
Shionoya’s group has created silver (I) coordinated assemblies which change
conformations with differing ligand to metal ratios(2). By either titrating in additional
silver ion or removing excess silver with a cryptand, the assemblies can change shape.
These different conformations have different binding affinities to guest molecules. By
exploiting this, guest molecules can be delivered to or removed from a specific
environment by changing the conformation of the cavitand.
Since Cram’s creation of extended cavitand structures in 1982(6), much interest
has been peaked in the possibilities they present for host/guest interactions. It has been
established that unsubstituted resorcin[4]arenes form a hexameric structure with
octahedral geometry in water-saturated organic solvent and the solid state, and guest
exchange thermodynamics and kinetics
have been studied(7). Resorcin[4]arene
structures can be modified on the upper
and lower rims, and these modifications
can have an effect on the conformation of the molecule, as well as solubility in various
solvents(3). There are two typical conformations for resorcin[4]arenes with aromatic
modifications on the upper rim: the vase, which has C4v symmetry with all aromatic arms
up, and the kite conformation which has C2v symmetry and the aromatic arms pointing
away from each other. The two forms can be easily distinguished by 1H NMR
spectroscopy. The vase conformation has its methine signal at δ= ~6 (ppm). The kite has
Depictions of the C4v vase (left) and C2v kite (right) conformations of resorcin[4]arene-based cavitands.
7
its methine peak at δ= ~3.5 (ppm). It has been established by Cram that the barrier for
interconversion between vase and kite conformations is approximately 10-12 kcal mol-1
for non-hydrogen bonding cavitands(6).
By controlling the conformation of the capsules, the
size and shape of the inside cavity is well-defined.
Hydrogen bonds are an excellent candidate because they can
be sensitive to acid and base. Alcohol functionalities can be
deprotonated by base, and amine functionalities can be
protonated by acid, and the resulting alkoxy or ammonium
salts behave differently than do the original alcohol or amine.
Rebek et al. have established the ability of rigid hydrogen
bonded capsules to bind strongly and selectively to guest
molecules(4). In the case of Rebek’s
octa-amido cavitand, the amide groups
form a belt of hydrogen bonds around
the top of the cavitand, essentially
holding the arms together. These
cavitands have a resorcinarene base and
have an open end at the top. Even with
an open end, the cavities bind strongly
to guests such as adamantanes, [2,2]
paracyclophanes, and toluamides. These cavitands have a higher energetic barrier for
interconversion between the vase and kite conformers than do non-hydrogen bonded
Top and side views of octanitro cavitand.
Diagram showing guest exchange and racemization of hydrogen-bonding cavitands
8
cavitands. The calculated barrier for vase-to-kite interconversion for Rebek’s cavitands
is 17 kcal mol-1. The extra 5 to 7 kcal mol-1 is attributed to the strength of the eight
hydrogen bonds, which typically have a bonding strength of 1 to 2 kcal mol-1 in organic
solvent. Studies have shown that guest exchange occurs only through the kite
conformation, and that guests stay firmly in the cavitand when it is in the vase
conformation.
By designing structures that can form dimers in organic solvents via
intermolecular hydrogen bonds, closed cylindrical capsules can be formed(3). These
structures are held together by a series of hydrogen bonds around the center of the
cylinder. Such capsules are able to protect reactive guest molecules such as benzoyl
peroxide from their environment. Upon addition of a more polar solvent (in this case
DMF), the hydrogen bonds are broken up,
leading to a dissociation of the dimer, and the
guest is free to react with other compounds
present. More recently, it has been shown that
the length of such cylindrical capsules can be
extended by insertion of glycoluril dimers
between cavitands(8). Here too, hydrogen
bonding is the force which holds together the
cylinder.
Resorcin[4]arenes have been functionalized with boronic acid functionalities, in
an attempt to mediate sugar transport across membranes. It was found that these
structures can mediate transport of fructose across a lipid bilayer, without any loss of the
Diagram showing dimerization of two cavitands to form cylindrical capsule.
9
cavitand from the bilayer. These cavitands can
selectively transport fructose, while not
transporting sucrose, and transporting only
small percentage of glucose. The number of
boronic acid functionalities can be controlled
easily, as well as the relative positions of the boronic acids to each other.
Even larger synthetic capsules have been created. Many structures which contain
self-recognizing glycouril units have been prepared and described in the chemical
literature. By combining a resorcin[4]arene backbone with glycouril arms in organic
solvent, a dimeric structure capable of encapsulating a cryptand-metal complex was
formed(10). This dimeric structure has in internal volume of approximately 950 Å3.
“Superbowl” structures have also been synthesized by covalently linking five
resorcinarene cavitands, with one cavitand acting as a base, and the other four acting as
walls(11). This large cavitand has an estimated internal volume of approximately 1375 Å3,
Structures of glyocouril linked
resorcinarene (left) and superbowl (right). The superbowl structure is
shown with four ethanol and one
chloroform guest molecules inside.
Boronic acid functionalized cavitand capable of sugar transport across lipid bilayers
10
and can encapsulate four methanol molecules within each wall resorcinarene cavity and
one chloroform molecule in the base cavity, determined by single crystal x-ray analysis.
Synthetic cavitands are also
capable of mediating chemical
transformations, such as cycloaddition and
rearrangement reactions. It has been
reported that the dimeric cylindrical
capsule investigated by Rebek is capable
of mediating a reaction between phenylacetylene and phenyl azide(12). This reaction
takes place slowly at room temperature in solution, with a rate constant of 4.3 x 10-9 M-1
s-1. If both reactants are present in 1M concentrations, this equates to a half-life of
several years. By encapsulating both components in their dimeric system, it was shown
that the reaction rate is increased by a factor of 240 (for the calculated concentrations in
the encapsulated species). More importantly, the reaction that takes place in the capsule
is stereospecific. The reaction between phenyl azide and phenylacetylene in solution
give a mixture of two products: 1,2-diphenyl-1,2,3-triazine and 1,4-diphenyl-1,2,3-
triazine. The reaction mediated by the capsule gives only the 1,4-diphenyl-1,2,3-triazine
product. Although the reaction is not catalytic (the products are not released by the
capsule), the reaction is stereospecific and the reaction rate is accelerated. There is also
evidence that water-soluble cavitands are capable of mediating reactions(13), that
resorcin[4]arene cavitands with porphyrin functionalities can catalyze chemical
reactions(14), and that amide-containing resorcin[4]arene cavitands can accelerate the
Mixing and reaction of encapsulated guest molecules. 1H NMR shifts are present next to characterizing proton signals for each species.
11
Menshutkin Reaction (alkylation of tertiary amines to form quaternary ammonium salts)
(15).
Where do we go from here? We know from nature that structure leads to
function. This is apparent in enzymes. We also know that having a well-defined cavity
allows for selective encapsulation and controlled release, and can even mediate selective
transport of specific target molecules. By controlling the conformation of our host
molecules, we hope to control the ability of these molecules to uptake and release guests,
which could be very useful in the areas of drug delivery and also in scavenging for
harmful compounds. By building molecules that are responsive to external stimuli, we
have the potential to influence their effects on their surroundings.
Our research group
has been working the area
of supramolecular
chemistry for nearly two
years now. Our studies
involve resorcin[4]arenes,
the same class of
compounds studied by Cram and Rebek, among others. We have created
resorcin[4]arene based-cavitands that have an organic-soluble base, a spacing aromatic
linker, and different functionalized gates with potential to control guest uptake and
release kinetics. The gate of main interest is a phenyl group with an amide functionality
at the 3-position and a methoxy group at the 5-position. We initially expected the amide
to hydrogen bond to the oxygen of the methoxy group. However, we found that the
Representative drawing of cavitand 1, showing all three designed features: organic soluble base, aromatic linker, and functionalized gate.
N N
NO O
OO O
OOO O O
C11H23C11H23C11H23 C11H23
H HHH
N N
NO O
N N
NO O
N N
NO O
Functionalized gate
Aromatic linker
Organic-soluble base
R RRR
12
amide groups hydrogen bond to each other, forming an assembly with C2 symmetry.
This was determined by 1H NOESY spectroscopy. The 1H NMR chemical shift of the
methine proton indicates that the hydrogen-bonding assembly is in the vase
conformation(16).
Protonation and solvent effects on the conformation of
the cavitand were then explored. It was found that addition of
triflouroacetic acid (TFA) greatly slows the equilibrium
between two enantiomeric conformations of the cavitand. The
origin of the stereochemistry is in the local directional chirality
of the hydrogen bonds between gates. At room temperature,
separate proton signals for the amide protons are seen. As the temperature is raised over
40°C, the equilibrium process occurs so rapidly that an average structure is observed,
with C4 symmetry. Incremental addition of a strong hydrogen-bond acceptor d6-DMSO
to a CDCl3 solution of the tetra-amido cavitand promoted a complete conversion of the
existing vase to its corresponding kite conformation; the resonance for the methine proton
shifted from 5.7 to 3.5 ppm after ~2200 equivalents DMSO-d6 were added. A second
variation of the capsule was synthesized, with t-Boc protecting groups on the aniline
nitrogen. These capsules have not been studied as extensively, due to the promising
initial results of the amide based cavitand, and the instability of t-Boc protecting groups
to TFA. To prove the results from the amide-based structure result from hydrogen
bonding, similar experiments must be performed on a similar structure, without hydrogen
bonding present. If the cavitand does not change conformation upon addition of DMSO-
d6, and the structure changes conformations in the presence of acid, it is very probable
H3CO X
N
X=NHAc, NHt-Boc, NO2
Potential gate structures
13
that the behavior seen in the amide-based cavitand is due to hydrogen bonding. The
following syntheses and experiments are directed towards exploring the behavior of a
non-hydrogen bonded system, and proving the results described above.
14
Chapter II. Results and discussion
We initially desired to create a cavitand with methyl groups at the 4-position of the
aromatic gates, and the effect of the methyl groups on guest exchange. Thusly, we began
our synthesis of the gate portion of the cavitand from 3,5-dinitro-4-methylbenzoic acid
(2). After esterification, one of the nitro groups was reduced by iron and hydrochloric
acid (4). The resulting amine was transformed to an alcohol (6) by diazonium
substitution via a diazonium tetraflouroborate salt (5). By using this intermediate we
were able to greatly improve the overall yield of this step, compared to a previous
procedure which called for isolating a diazonium bisulfate intermediate. This was
followed by methylation of the alcohol with dimethyl sulfate to give (7). The nitro-
methoxy ester was then transformed to an amide (8) by reaction with methanolic
ammonium hydroxide. The amide was then transformed to an amine (9) by the Hoffman
Rearrangement. However, the synthetic process was long, and yields were poor for many
of the intermediate steps, and even those that gave good yields were often inconsistent.
This led us to seek an alternative method for the synthesis. We uncovered a procedure
which employed nucleophilic aromatic substitution on 3,5-dinitrobenzoic acid using
HMPA and lithium methoxide(17). However, the reaction did not work on the methyl-
substituted aromatic system. We hypothesized that the reaction did not work due to the
steric hindrance of the adjacent methyl group combined with the deactivation of the ring
to nucleophilic attack due to the methyl substituent. Since the reaction worked with the
non-methylated compound and we desired to use the compound in eventual studies, the
decision was made to proceed with this derivative. By directly synthesizing the methoxy
derivative, four synthetic steps were eliminated.
15
Synthesis of methyl-substituted gate
O2N NO2
COOEt
Fe/AcOH
O2N NH2
COOEt
1) HBF4/MeOH
2) n-Bu-ONO
O2N N2
COOEt
H2SO4/ H2O
CuSO4/Cu2O
O2N OH
COOEt
K2CO3/Acetone
O2N OMe
COOEt
NH4OH/MeOH
O2N OMe
CONH2
NaOBr
NaOH
O2N OMe
CONHBr
O2N OMe
NH2
Me2SO4
O2N NO2
COOH
EtOH/ HCl
99% 95.8%
81.3% 86.8%
57.1%
Na2CO3, H2O
83.2%
Not isolated
99%
BF4
3 4
5 6
7 8
9
2
16
I. Synthesis of cavitand 1: The resorcin[4]arene (10) was prepared using resorcinol and
dodecanal in an acid catalyzed condensation. The aromatic linker was synthesized using
a previously published procedure(18), which calls for permanganate oxidation of 2,3-
dichloroquinoxaline in boiling water to form the dicarboxylic acid (11). The diacid is
then reacted with refluxing thionyl chloride for half an hour to form anhydride (12) in
75% yield. The gate is synthesized from 3,5-dinitrobenzoic acid in four steps. This is
accomplished by first performing a nucleophilic aromatic substitution with freshly
prepared lithium methoxide in HMPA to give (13) in 98% yield(17). The second step
towards the gate is a base-promoted esterification with potassium carbonate and dimethyl
sulfate in acetone, producing (14) in 84% yield, followed by amidation with ammonium
hydroxide over 7 days to afford amide (15) which crystallized out of solution in 75%
yield. This step is followed by a Hoffman rearrangement using a freshly prepared
sodium hypobromite solution, followed by quench with sodium bicarbonate, to give
aniline (16) (19). This reaction was very inconsistent. If the intermediate bromoamide
was not completely dried on high vacuum pump, the reaction would yield starting
compound 7. When the reaction went forward it worked well, giving yields upwards of
75%. Dichloroimide (17) is formed by condensation of gate 16 and linker 12 by mixing
in dry THF, addition of catalytic DMF, oxalyl chloride, and quenching the acid byproduct
with pyridine to give dichloroimide 17 as a pure precipitate in 75% yield. This imide is
mixed with resorcin[4]arene base 10 in dry DMF and dry TEA according to the
procedure provided by Rebek et. al(19). Cavitand 1 is isolated in 68.6% yield after
purification by column chromatography.
17
Chapter III. Titration Experiments
A. DMSO-d6 titration
Following the synthesis and characterization of the cavitand 1, we proceeded to explore
the effects of changing solvent polarity on the conformation of the nitro cavitand. Our
sample was prepared by evaporation of residual solvent on a Kugelrohr apparatus
overnight at 50°C. The sample was then dissolved in dry CDCl3, which was distilled
over calcium hydride and stored over 4Å molecular sieves in a dessicator. The titration
was performed by incremental addition of DMSO-d6 to the NMR tube, mixing, and
monitoring the chemical shift of the methine proton. Initial additions were of a 4:1 (v/v)
solution of CDCl3: DMSO-d6. After addition of 15 equivalents of DMSO, pure DMSO-
d6 was added portion-wise. Additions ranged from 100 to 200 equivalents at a time, up to
2215 equivalents. The CH chemical shift was recorded, and was found to range from
4.4952 to 4.1951 (ppm). This movement of chemical shift (∆δ=0.3 ppm) is not very
significant when one takes into consideration the 2 ppm difference between the vase and
kite conformations of resorcinarene cavitands.
DMSO-d6 titration experiments of cavitand 1(blue diamonds) and tetra-amido cavitand
(green squares) in CDCl3
3
3.5
4
4.5
5
5.5
6
0 500 1000 1500 2000 2500equivalents DMSO-d6
chem
ical
sh
ift
(pp
m)
18
B. TFA titration
We also desired to study the effects of acid on the conformation of our cavitand.
Triflouroacetic acid (TFA) is a strong acid (pKa = 0.5) capable of protonating the
nitrogen atoms of pyrazine rings similar to those present in our compound. The sample
was prepared by removal of residual solvent on a Kugelrohr apparatus at 50°C overnight.
The solid was then dissolved in dry CDCl3. Triflouroacetic acid was added to the
solution incrementally, and the chemical shift of the methine proton was monitored. The
cavitand was found to be very sensitive to addition of acid; the chemical shift of the
methine proton moved towards the vase conformation upon addition of acid. After
addition of ~90 equivalents, the chemical shift approached its lower limit. In
comparison, the tetra-amido cavitand did not undergo conformational change; the
chemical shift of the methine proton stayed at ~5.6. These results confirm our
expectations that hydrogen bonds hold together the amido cavitand. We found that the
conformation of cavitand 1 is not sensitive to changes in solvent polarity (while the
amido-cavitand is sensitive), and that it is sensitive to addition of TFA (while amido-
cavitand is not).
TFA titration experiments of cavitand 1 (bluediamonds) and tetra-amido cavitand (green
squares) in CDCl3
3
3.5
4
4.5
5
5.5
6
0 50 100 150 200 250 300 350 400 450mol equiv TFA
ch
em
ica
l s
hif
t (p
pm
)
19
Chapter IV. Conclusions and future work
The research described above has given insight into the effects of solvent polarity and
acid on the conformation of novel gated resorcin[4]arene based cavitands. The studies
presented above effectively prove our initial assumptions about the effect of hydrogen
bonding in our cavitand systems. A control cavitand of similar molecular weight and
size, and without hydrogen bonds, was synthesized and characterized by 1H NMR. The
average conformation of the nitro-cavitand was found to be between the two limits of
cavitand conformation (vase and kite). The equilibrium between the two conformations
of the studied compound is fast on the NMR timescale at room temperature, and the
chemical shift present is representative of the average molecular conformation. The
conformation of the nitro cavitand was not greatly effected by addition of polar solvent,
and is very sensitive to acid addition. This leads us to the conclusion that the hydrogen
bonds present in the amide-substituted cavitand hold it in the vase conformation. The
conformation of the hydrogen-bonded cavitand is sensitive to solvent polarity, and not
sensitive to acid addition. We can confidently say that the control experiments presented
in this paper prove our initial assumptions, since solvent polarity had little effect on a
non-hydrogen bonding system, and acid addition had a pronounced effect.
Future studies will include finding a suitable guest molecule for our systems. We
can then study the effect of solvent polarity and acid addition on the release of guest
molecules. By building stimuli-responsive molecular cavitands, we can hope to control
guest uptake and release, and possibly mediate chemical transformations within the free
volume present in such cavitands. We also seek to study different variations of such
cavitands. Currently, our group is performing synthesis directed toward deeper cavitands
20
based on tris-norbornene cavitands. We will also study the effects of adding a methyl
group to the 4 position on the gate structure, differing alkyl chain length, and also study
covalently bound structures and metal-coordinated structures. The field of host/guest
chemistry and molecular recognition has many possibilities.
21
Chapter V. Experimental
General Procedures. All chemicals were purchased from commercial sources, and used
as received unless stated otherwise. All solvents were dried prior to use according to
standard literature protocols. Chromatography purifications were performed using silica
gel 60 (Sorbent technologies 40-75 μm, 200 x 400 mesh). Thin-layer chromatography
(TLC) was performed on silica-gel plate w/UV254 (200 μm). Chromatograms were
visualized by UV-light, 1H and 13C NMR spectra were recorded on Bruker DRX 500
MHz and DPX250 spectrometers. All chemical shifts were measured relative to residual
solvent peaks. Samples were prepared using CDCl3, CD3COCD3, and CD3SOCD3
purchased from Cambridge Isotope Laboratories. The chemical shift values are expressed
as δ values and the coupling constants values (J) are in Hertz (Hz). The following
abbreviations were used for signal multiplicities: s, singlet; d, doublet; t, triplet; m,
multiplet; and br, broad.
OH OHOHHO
HO OH HO
RRR
R
H HHH
HO OH
+C11H23 H
OHClEtOH
10
Dodecyl resorcin[4]arene (10). Resorcinol (5.0g, 45.4mmol) was dissolved in ethanolic
hydrochloric acid (6.31mL conc. acid in 19mL absolute ethanol). To this solution
dodecanal (8.37g, 45.4mmol) in ethanol (12.6mL) was added dropwise. This solution
was heated at 80ºC for 21h, after which it was cooled, and the crystalline product was
filtered off and washed with cold methanol. The product was then purified by
recrystallization from methanol, yielding 8.992g (71.6%) of product 10. 1H NMR
22
(acetone-d6, 250 MHz) δ (ppm) = 8.41 (s, 8H, OH), 7.52 (s, 4H, Ar-H), 6.23 (s, 4H, Ar-
H), 4.30 (t, J=7.75 Hz, 4H, CH), 2.28 (q, J= 6.25Hz, 8H, CH2), 1.29 (m, 72H, CH2), 0.88
(t, J= 5Hz, 12H, CH3).
N N
Cl Cl
KMnO4
H2O, 90 C N N
COOHCOOH
Cl Cl
11
5,6-dichloropyrazine-2,3-dicarboxylic acid (11). 5,6-Dichloroquinoxaline (500mg,
2.57mmol) was added to boiling water (40mL). Potassium permanganate (2.65g,
16.8mmol) was added to this solution in portions, and the reaction mixture heated at 98ºC
for 2 hours. The mixture was filtered and the reaction flask was washed with an
additional 100mL of water, boiled, and filtered. The combined filtrates were acidified by
addition of concentrated hydrochloric acid (5mL), and the water was removed in vacuo.
The resulting solid was washed with acetone, filtered, and the acetone removed in vacuo
to give 294.2mg (49.5% yield) of pure product 11. 1H NMR (acetone-d6, 250 MHz) δ
(ppm) = 7.94 (br s, 2H, COOH); 13C NMR (acetone-d6, 63 MHz) δ (ppm) = 162, 147,
142.
23
N N
COOHCOOH
Cl Cl
SOCl2
N N
Cl Cl
OO O
11 12
Reflux
5,6-dichloropyrazine-2,3-dicarboxylic acid anhydride (12). Thionyl chloride (2 x 1mL)
was used to dissolve 11 (294.3mg, 1.24mmol). The reaction mixture was refluxed for 30
minutes in a 100mL round bottom flask under a positive pressure of argon. The thionyl
chloride was then removed by high vacuum pump. The solid was extracted with ethyl
acetate and the organic solvent evaporated, yielding 204.8mg product 12 (75.3%). 13C
NMR (acetone-d6, 125 MHz) δ (ppm) = 158, 155, 144.
Preparation of lithium methoxide
Lithium metal (1g, 144mmol) was added in small portions to methanol (60mL) under
argon. After addition, the reaction mixture was allowed to stir for 2h, after which the
solvent was removed. The product was dried on high vacuum pump and stored in a
dessicator.
O2N NO2
COOH
LiOMe
HMPA, 80 C
O2N
COOH
OMe
13
3-Methoxy-5-nitrobenzoic acid (13). Lithium methoxide (5.0g, 132mmol) was dissolved
in dry HMPA (40mL) under argon. 3,5-dinitrobenzoic acid (7.0g, 33mmol) was added to
24
this solution in small portions. The reaction mixture was heated to 80ºC for 14h. The
solution was poured into an ice cooled solution of sulfuric acid (12mL conc. sulfuric acid
in 150mL H2O). This solution was extracted with diethyl ether, the organic phase
washed with brine, dried over Na2SO4, filtered, evaporated, and filtered through a thin
pad of silica (SiO2, ethyl acetate/hexanes 4:1), to yield 6.4g acid 13 (98% yield). 1H
NMR (DMSO-d6, 250 MHz) δ (ppm) = 13.69 (br s, 1H, COOH), 8.19 (dd, J=1.25, 2 Hz,
2H, Ar-H), 7.92 (dd, J= 2, 2.5 Hz, 1H, Ar-H), 7.80 (dd, J=1.25, 2.5 Hz, 1H, Ar-H), 3.92
(s, 3H, OCH3).
O2N
COOH
OMe O2N
COOMe
OMe
13 14
K2CO3, acetone
(CH3)2SO4
Methyl 3-Methoxy-5-nitrobenzoate (14). Acid 13 (200mg, 1.01mmol) was added to a
solution of dry acetone (10mL) and potassium carbonate (491mg, 3.55mmol) under an
argon atmosphere. To this solution dimethyl sulfate (290μL, 3.04mmol) was added
dropwise. The reaction mixture was stirred for 14h at room temperature. The solvent
was removed in vacuo, and the residue was purified by flash chromatography (SiO2,
hexanes/ethyl acetate 5:1) to yield 180mg (84.4% yield) of the product ester 14. 1H
NMR (CDCl3, 250 MHz) δ (ppm) = 8.45 (dd, J=1.5, 1.75 Hz, 1H, Ar-H), 7.91 (dd, J=2,
1.75 Hz, 1H, Ar-H), 7.88 (dd, J=1.5, 2 Hz, 1H, Ar-H), 3.98 (s, 3H, OCH3), 3.94 (s, 3H,
OCH3).
25
NH4OH
7 Days
O2N
CONH2
OMe
15
14
3-Methoxy-5-nitrobenzamide (15). Ester 14 (1.79g, 9.125mmol) was dissolved in
methanol (19mL), and to this solution was added concentrated ammonium hydroxide
(13mL). The reaction mixture was allowed to stand without stirring for 6 days, during
which the product amide 7 precipitated out of solution as pale yellow crystals in 75.5%
yield. The crystals were filtered off and used without further purification. 1H NMR
(CDCl3/acetone-d6, 250 MHz) δ (ppm) = 8.22 (d, J=1.25 Hz, 1H, Ar-H), 8.05 (br s, 1H,
NH), 7.71 (d, J=1.25 Hz, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 7.08 (br s, 1H, NH), 3.76 (s, 3H,
OCH3).
O2N
CONH2
OMe
1) NaOBr, MeOH
2) NaHCO3, H2O
O2N
NH2
OMe
15 16
3-Methoxy-5-nitroaniline (16). Amide 15 (50mg, 0.255mmol) was dissolved in
methanol (3mL). A solution of NaOBr (0.5mL, freshly prepared from 1.2g NaOH and
0.3mL Br2 in 10mL H2O) was added dropwise at room temperature. The reaction
mixture was stirred for 1h, after which the solvent was removed in vacuo. The yellow
solid was further dried on high vacuum until no residual solvent remained. A dilute
26
solution of sodium bicarbonate (31 mg) in water (4.3mL) was added. The reaction
mixture was slowly heated to 75ºC and stirred for 1h. The reaction mixture was filtered
to give aniline 16 as an orange solid (31.6 mg, 73.7% yield). 1H NMR (CDCl3, 250
MHz) δ (ppm) = 7.14 (s, 1H, Ar-H), 7.13 (s, 1H, Ar-H), 6.48 (t, J= 2 Hz, 1H, Ar-H), 3.83
(s, 3H, OCH3), 1.55 (br s, 2H, NH2).
1) THF, 4h
2) DMF, (COCl)2, 2h
3) Pyr, overnight
N
N
Cl
Cl
N
O
O
NO2
OMe
17
16 + 12
5,6-dichloropyrazine 3-Methyl-5-Nitrophenyl imide (17). A solution of aniline 16
(125mg, 0.743mmol) and anhydride 12 (162mg, 0.738mmol) in dry THF (14mL) was
stirred under argon at room temperature. After 4h, dry DMF (4μL) was added, followed
by oxalyl chloride (2 x 76μL). This mixture was stirred for 2 h, after which pyridine (2 x
140μL) was added. This reaction mixture was then stirred overnight at room
temperature. The product was checked by TLC (benzene/acetone 10:1). The product
was then filtered through a thin pad of silica gel (SiO2, benzene/acetone 10:1) to give
product 17 in 75.7% yield. 1H NMR (CDCl3/acetone-d6) δ (ppm) = 7.95 (dd, J=2, 2 Hz,
1H, Ar-H), 7.83 (dd, J=2, 2 Hz, 1H, Ar-H), 7.47 (dd, J=2, 2 Hz, 1H, Ar-H), 3.98 (s, 3H,
OCH3); 13C NMR (CDCl3, Acetone-d6, 125 MHz) δ (ppm) = 162, 161, 153, 150, 144,
133, 120, 114, 108, 56.
27
OH OHOHHO
HO OH HO
RRR R
H HHH
N
N
Cl
Cl
N
O
O
NO2
OMe
+DMF, TEA
80 C, overnight
N N
NO O
O2N OMe
OO O
OOO O O
C11H23C11H23C11H23 C11H23
H HHH
N N
NO O
O2N OMe
N N
NO O
O2N OMe
N N
NO O
O2N OMe
1
4 x
Tetranitro cavitand (1). Freshly distilled TEA (33μL) was added to a solution of imide
17 (15mg, 0.0406mmol) and resorcin[4]arene 10 (9mg, 0.001813mmol) in dry DMF
(1.7mL). The reaction mixture was stirred under argon at room temperature for 3h, after
which the temperature was raised to 60ºC and stirred for
9h. The solvent was removed in vacuo, and the residue
purified by column chromatography (SiO2,
benzene/acetone 95:5), to give cavitand 1 (12.3mg, 68.6%
yield). 1H NMR (CDCl3, 500 MHz) δ (ppm) = 7.82 (dd,
J=2, 2 Hz, 1H, H2), 7.69 (dd, J=2.25, 2 Hz, 1H, H1), 7.63
(s, 1H, H5), 7.22 (dd, J=2.25, 2.0 Hz, 1H, H3), 7.05 (s, 1H,
H4), 4.49 (1H, t, J=7.5 Hz, 1H, H6), 3.83 (s, 3H, OCH3),
2.17 (m, 2H, H7), 1.26 (m, 18H, H8), 0.87 (t, J=11.5 Hz,
3H, H9).
N
N N
O O
H6H2C
C9H18
H3C
O2N O
O O
CH3
H4
H5
H1
H3 H3
H7
H8
H9
Cavitand proton assignments
28
Chapter VI. References and Footnotes
1) Jasat, A and Sherman, J. C. Chem. Rev. 1999, 99, 931-965
2) a) S. Hiraoka, K. Harano, M. Shiro, and M. Shionoya. Angew. Chem. Int. Ed. 2005,44, 2727-2731
b) S. Hiraoka,T. Yi, M. Shiro, M. Shionoya. J. Am. Chem. Soc. 2002, 124, 14510-14511.
3) S. K. Körner, F. C. Tucci, D. M. Rudkevich, T. Heinz, J. Rebek, Jr. Chem. Eur. J. 2000, 6, 187-195.
4) D. M. Rudkevich, G. Hilmersson, J. Rebek, Jr. J. Am. Chem. Soc. 1997, 119, 9911-9912.
5) V. Maslak, Z. Yan, S. Xia, J. Gallucci, C. M. Hadad, J. D. Badjic. J. Am. Chem. Soc. 2006, 128, 5887-5894
6) J. R. Moran, S. Karbach, D. J. Cram. J. Am. Chem. Soc. 1982, 104, 5826-5828.
7) a) A. Shivanyuk J. Rebek, Jr.. J. Am. Chem. Soc. 2003, 125, 3432-3433. b) M. Yamanaka, A. Shivanyuk, J. Rebek, Jr.. J. Am. Chem. Soc. 2004, 126,
2939-2943.
8) D. Ajami and J. Rebek, Jr.. J. Am. Chem. Soc. 2006, 128, 5314-5315.
9) T. M. Altamore, E. S. Barrett, P. J. Duggan, M. S. Sherburn, and M. L. Szydzik. Org. Lett. 2002, 4, 3489-3491.
10) A. Lützen, A. R. Renslo, C. A. Schalley, B. M. O’Leary, J. Rebek, Jr. J. Am. Chem. Soc. 1999, 121, 7455-7456.
11) E. S. Barrett, J. L. Irwin, A. J. Edwards, M. S. Sherburn. J. Am. Chem. Soc. 2004, 126, 16747-16749.
12) J. Chen and J. Rebek, Jr. Org. Lett. 2002, 4, 327-329.
13) R. J. Hooley, H. J. Van Anda, J Rebek, Jr. J. Am. Chem. Soc. 2006, 128, 3894-3895.
14) S. Richeter and J. Rebek, Jr.. J. Am. Chem. Soc. 2004, 126, 16280-16281.
15) B. W. Purse, A. Gissot, and J. Rebek, Jr. J. Am. Chem. Soc. 2005, 127, 11222-11223.
29
16) Z. Yan, V. Maslak, Y. Chang, D. Mayo, J. D. Badjić. Org Lett. Currently submitted for review.
17) Aust. J. Chem. 1981, 34, 1319.
18) D. J. Cram, H. J. Choi, J. A. Bryant, C. B. Knobler. J. Am. Chem. Soc. 1992, 114, 7761.
19) P. Y. Johnson, R. Pan, J. Q. Wen, and C. J. Halfman. J. Org. Chem. 1981, 46, 2053.
20) For an excellent review of supramolecular encapsulation, see Angew. Chem. Int. Ed.2002, 41, 1488-1508.
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